Since its inception in 1991, the Brain Trauma Research Center at the University of Pittsburgh has studied the effects of therapeutic moderate hypothermia in laboratory models of contusion and epidural compression injury in a randomized clinical trial. In the laboratory we have determined that hypothermia significantly reduces the volume of brain tissue damaged following injury, and have better defined the role of excitatory amino acids and interleukins in this protective effect. Other investigations have implicated cellular mediators of inflammations as a possible cause for post-traumatic hyperemia. The clinical studies found that hypothermia causes a significant reduction in intracranial pressure following severe traumatic brain injury. This positive effect of hypothermia was associated with a sustained decrease in the cerebrospinal fluid levels of neurochemical mediators of secondary brain injury (interleukin-1 beta, glutamate). The clinical studies also have defined the time course of cerebral blood flow and metabolic changes that occur following trauma. In this competitive renewal application we propose to continue our investigations of the mechanisms of secondary brain injury and the clinical effects of moderate hypothermia through a series of highly focused research projects. The projects have been chosen based on the concept that future improvement in outcome after traumatic brain injury will rely on a thorough understanding of the mechanisms of secondary brain injury. The laboratory investigations will examine the role of reactive oxygen species, cytokines, neurotrophic factors, and cellular mediators of inflammation in mediating secondary brain injury and post- traumatic hyperthermia. The clinical investigations will use in vivo microdialysis and several cerebral blood flow monitoring techniques to define the prevalence of post-traumatic ischemia and the effect of moderate hypothermia on that prevalence. The clinical projects also will determine whether hypothermia will lead to measurable brain tissue preservation. These projects will accomplish several clinically relevant goals: define critical mechanisms of secondary brain injury, determine characteristics of post-traumatic ischemia, and help to establish the efficacy of therapeutic moderate hypothermia. The center will maintain a comprehensive head injury database containing all data elements recommended by the NINDS Head Injury Centers Database Task Force. In addition, the Center will continue its educational training activities through annual head injury meetings, monthly seminars, and the neurotrauma fellowship training program.